Abstract Injection drug use continues to be an important factor in HIV-1 infection and transmission worldwide. Over 25% of AIDS cases in the US are currently attributable to injection drug use. HIV infection in injection drug users (IDUs) also represents a growing problem in southeast Asia and eastern Europe: In China, IDUs account for more than 50% of HIV-1 infections. Extensive population studies have demonstrated that polymorphisms in host genomes encoding chemokines and their receptors are associated with altered rates of HIV-1 infection and disease progression. However, these studies have mainly been conducted in Caucasian and African American populations. Clearly, additional genetic factors may exist in various racial and ethnic populations that can further affect HIV-1 infection and/or disease progression. Recently, we observed high frequencies of a natural complete deletion allele of the cytidine deaminase APOBEC3B (A3B) in our IDU study population in southern China. We found that people who are homozygous for the A3B deletion are significantly more resistant to HIV-1 infection than those who are homozygous for the wild-type A3B alleles (odds ratio=3 [95% confidence interval 1.2-7.5]). Furthermore, multiple regression analysis revealed significant positive associations between A3B expression and viral load set-points. APOBEC3 cytidine deaminases such as A3B are highly expressed in human T lymphocytes and macrophages. These enzymes can potentially increase HIV-1 variation by inducing cytidine deamination (C to U) during reverse transcription, resulting in G-to-A mutations in the HIV-1 genome. Certain APOBEC3 proteins also inhibit HIV-1 infection, and HIV-1 has developed a counter-defense by encoding the Vif protein. Amazingly, A3B is the only cytidine deaminase that can mutate the HIV-1 genome and be spared by HIV-1 Vif. In this application, we propose to further characterize the effects of the A3B deletion by carrying out the following specific aims: Aim 1. To further evaluate the effect of a homozygous deletion of A3B on HIV-1 infection. We will examine the effect of this naturally occurring deletion on HIV-1 infection over time among seronegative IDUs to determine whether the deletion confers persistent protection against HIV-1 infection. We will also examine more study subjects in our existing cohort to further substantiate the effect of the deletion on HIV-1 infection with the CRF08 strain. Aim 2. To determine the effect of a complete homozygous A3B deletion on infection with different HIV-1 subtypes. In particular, we will examine its effect on CRF01 and CRF08 infection among IDUs in our established cohorts. These studies will address the question of whether the effect of A3B deletion on HIV-1 infection is HIV-1 strain specific. Aim 3. To perform longitudinal observations on the effect of A3B deletion alleles on HIV-1 disease progression. The disease progression markers will be compared in HIV-1-infected individuals who are homozygous for the A3B deletion and in HIV-1-infected individuals who have at least one intact A3B gene. We will also compare the influence of the A3B deletion on HIV-1 transmission and disease progression to those of polyphorphisms in other host genetic factors, including HLA alleles, chemokines, and chemokine receptors. The proposed research is both innovative and significant in that it utilizes a unique population of subjects to dissect the influence of novel host factors on HIV-1 transmission and disease progression. A major advantage is the ability to study viral transmission and disease progression in a nascent epidemic area where HIV-1 infection has been closely followed from the beginning. Investigation of host genetic polymorphism in an understudied population by established researchers who have had extensive experience in similar types of studies in Caucasians and African Americans is a further advantage. This study should provide critical insights into the complex interplay between viral, host genetic, and behavioral factors in HIV-1 transmission and pathogenesis and may provide us with critical information regarding the design of effective intervention strategies.